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NCT Number: NCT00556933

Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

This 2 x 2 sequential factorial study evaluates two potential improvements to the standard immunosuppression regimen used at the investigators' institution to prevent rejection of transplanted kidneys. These two potential improvements are each applied in sequence to half of the study patients, creating 4 study arms; the other half receive the standard treatment. The two potential improvements are:

1. Administering the immunosuppression induction agent rATG ("rabbit anti-thymocyte globulin") in a single dose at the time of transplantation, instead of in the usual series of 4 smaller doses over 6 days. 2. After 6 months, modifying the maintenance immunosuppression used to prevent rejection by replacing the drug tacrolimus with mycophenolate mofetil (MMF).

The two interventions, spaced sequentially six months apart, enable independent analysis of the two treatments so long as it can be shown that there is no synergistic interaction between them.

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Key information

Conditions

End-stage Renal Disease Chronic Disease Disease Attributes Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Diseases Kidney Failure, Chronic Male Urogenital Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Renal Insufficiency Renal Insufficiency, Chronic Urogenital Diseases Urologic Diseases

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Unversity of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

About this study

The two treatment innovations in this study of immunosuppression in kidney transplantation are aimed at making the transplanted kidney function sooner and last longer than is usual with standard immunosuppression regimens, but without increasing the likelihood of rejection.

The first innovation, delivering the induction agent rATG in a single large dose rather than as a series of smaller doses over 6-8 days, is expected to produce better graft function right away, possibly by reducing some of the injury to the kidney that accompanies the restoration of blood flow during transplantation ("reperfusion injury"). Some evidence has been developed by investigators elsewhere to suggest this will happen.

The second innovation, replacing tacrolimus with MMF after 6 months, is intended to eliminate a well-established major cause of ongoing toxic damage to the kidney. While tacrolimus does a good job of preventing rejection, the cost in continuing toxic injury to the kidney is high, leading inevitably to eventual graft failure, the inability of the transplanted kidney to continue filtering the blood and making adequate volumes of high-quality urine.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Primary renal transplant recipient for end-stage renal disease

Exclusion criteria

  • Recipient age < 18 years or > 65 years
  • Previous history of CMV disease
  • Hepatitis B and C recipients
  • Primary disease states that require steroids for immunosuppression
  • Re-transplant with immunological cause of renal or pancreas loss
  • Non heart beating donors
  • Recipient of pediatric en bloc kidneys
  • Recipient with a Panel Reactive Antibody (PRA) score >75%
  • Patients who have received 3 or more prior transplants, excluding pancreas
  • Patients who are past recipients of other solid organ transplants
  • Previous history of BK virus
  • Previous treatment with Thymoglobulin
  • Allergy to rabbits
  • Simultaneous Kidney/Pancreas transplantation

Treatment and study plan

rabbit anti-thymocyte globulin - single dose

Drug

A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.

Other names: Thymoglobulin, rATG

Mycophenolate mofetil

Drug

Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.

Other names: CellCept, MMF, mycophenolic acid, Myfortic

rabbit anti-thymocyte globulin - 4 doses

Drug

6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.

Other names: Thymoglobulin

sirolimus

Drug

Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection

Other names: Rapamune, rapamycin

Tacrolimus

Drug

Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.

Other names: FK506, ProGraf

Primary outcomes

  1. Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria).

    Time frame: Two years

    Protocol kidney biopsies collected at approximately 12 and 24 months were scored by a transplant renal pathologist blinded to treatment group assignment for evidence of rejection, BK virus nephropathy, antibody-mediated rejection, recurrent disease, inflammation, and Banff 2005 categories of chronic renal injury. Chronic injury categories were arteriolar hyaline thickening (ah), allograft glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and vascular fibrous intimal thickening (cv). Severity scores within each category could be 0 (<5%; none or minimal), 1 (>5% - <25%; mild), 2 (>25% - <50%, moderate), or 3 (>50%, severe). The proportions of patients in each severity grade (0, 1, 2, and 3) for both the individual categories and a composite were compared using Fisher's exact test.

  2. Average of Renal Function

    Time frame: Two years

    Calculated Glomerular Filtration Rate (GFR) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data; averaged values from months four through 24.

Secondary outcomes

  1. Safety Profile

    Time frame: Two years

    Number of events: cytomegalovirus (CMV) disease, opportunistic infections (bacteremia, abscess, pneumonia, fungal), Post-transplantation Lymphoproliferative Disorder (PTLD), wound healing problems within 30 days, and lymphoceles.

  2. Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents)

    Time frame: Two years

  3. Acute Rejection Per Kidney Biopsy (Banff Grading Criteria)

    Time frame: Two years

  4. Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation.

    Time frame: Seven days

  5. Graft Survival

    Time frame: Two years

    Graft failure = permanent return of patient to dialysis.

  6. Patient Survival

    Time frame: Two years

  7. Lymphoid Cell Sub-type CD3 Absolute Numbers

    Time frame: One year

  8. New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy

    Time frame: Two years

  9. New-onset Diabetes and Hyperglycemia After Transplantation (NODAT)

    Time frame: Six months

  10. Ratio of CD4/CD8 Lymphoid Cells

    Time frame: One year

Sponsors and collaborators

Lead sponsor

University of Nebraska

Other

Collaborators

  • Genzyme, a Sanofi Company

Registry information

Official study title

Prospective, Randomized 2 x 2 Factorial Trial of Rabbit Anti-thymocyte Globulin Induction (Single vs. Alternate Day Administration) at Renal Transplantation, With Delayed Calcineurin-inhibitor Withdrawal vs. Minimization

Important dates

Study start
2004
Primary completion
2011
Study completion
2011
First posted
Nov 12, 2007
Registry last updated
Sep 18, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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